致癌黴菌毒素對於細胞基因表現及訊號傳遞的影響

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Title:	致癌黴菌毒素對於細胞基因表現及訊號傳遞的影響
Authors:	劉秉慧 Liu, Biing-Hui
Contributors:	中山醫學大學生命科學系
Date:	2004
Issue Date:	2010-11-05T10:49:09Z (UTC)
Abstract:	Patulin (PAT), a mycotoxin produced by certain species of Penicillium and Aspergillus, is often detectable in moldy fruits and their derivative products. PAT led to. a concentration-dependent and time-dependent increase in phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human embryonic kidney (HEK293) cells, human peripheral blood mononuclear cells (PBMCs), and Madin-Darby canine kidney (MDCK) cells. Treatment of HEK293 cells with 5 μM and 0.05 μM PAT induced ERK1/2 phosphorylation after 30 min or 24 h, respectively. Treatment of human PBMCs for 30 min with 30 μM PAT also dramatically increased the phosphorylated ERK1/2 levels. The MEK1/2 inhibitor, U0126, but not MEK1 inhibitor, PD98059, suppressed ERK1/2 activation in both HEK293 and MDCK cells. In HEK293 cells, U0126-mediated inhibition of PAT-induced ERK1/2 phosphorylation resulted in a significant decrease in levels of DNA damage, expressed as tail moment values, in the single cell gel electrophoresis assay. Conversely, U0126 did not affect cell viability, lactate dehydrogenase release, and the DNA synthesis rate in PAT-treated cultures. Exposure of HEK293 cells for 90 min to 15 μM PAT elevated the levels of early growth response gene-1 (egr-1) mRNA, but not of c-fos, fosB, and junB mRNAs. These results indicate that in human cells, PAT causes rapid and persistent activation of ERK1/2 through the MEK2 pathway and this signaling pathway plays an important role in mediating PAT-induced DNA damage and egr-1 gene expression. 棒麴毒素(Patulin 簡稱PAT)是由 Penicillium和 Aspergillus 菌屬所分泌的黴菌毒素(mycotoxin)，通常在發霉的水果和再製品中被偵測出來。以棒麴毒素處理人類胚胎腎臟細胞株(human embryonic kidney cell 簡稱HEK293)、周邊血液單核球細胞(human blood mononuclear cells 簡稱PBMCs)和 Madin-Darby氏犬科腎小管細胞株(Madin-Darby canine kidney cell 簡稱MDCK)時，.著毒素濃度及處理時間的增加，會使上述細胞中的 extracellular signal-regulated protein kinases 1 and 2(ERK1/2)的磷酸化表現增加。將 HEK293細胞株分別以 μM及 0.05 μM的 PAT處理 30分鐘或 24小時，可以誘導 ERK1/2磷酸化的表達；而在人類 PBMCs中，以 30 μM PAT處理 30分鐘也可以得到 ERK1/2磷酸化增加的現象。在 HEK293及 MDCK細胞珠中使用 MEK1/2抑制劑-U0126足以抑制由 PAT所誘發的 ERK1/2活化，但是 MEK1的抑制劑-PD98059並不具有相同的效果。當利用 HEK293細胞株進行單細胞電泳實驗時，由 tail moment所得之數值發現 U0126 藉由抑制 ERK1/2的磷酸化表現，會顯著的降低 PAT所誘發之 DNA損傷的現象。然而 U0126的處理並不會影響 PAT所造成的細胞存活率、細胞膜完整性和 DNA合成速率等現象。以 15 μM處理 HEK293細胞株 90分鐘後，會顯著提高 early growth response gene-1 (egr-1) mRNA含量，但是並不會改變c-fos，fos B或是 junB 的 mRNA量。以上結果顯示，在人類細胞株中 PAT會藉由 MEK2造成 ERK1/2快速且持續的活化，而這一條訊息傳導的途徑，在 PAT所誘導 DNA damage和 egr-1 基因的表達中，扮演著重要的角色。
Appears in Collections:	[School of Biomedical Sciences] Research Project Report

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